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Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.

Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H - Mol Neurodegener (2010)

Bottom Line: SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information.PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

ABSTRACT

Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups.

Results: We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.

Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

No MeSH data available.


Related in: MedlinePlus

Aβ1-16 does not inhibit hippocampal long-term potentiation (LTP). (A) Control LTP elicited by three trains (20 impulses, 50 Hz) separated by 5 seconds. Data points are normalized field EPSP initial slope measurements ± standard errors of the mean. Average (n = 20) field EPSPs before and 60 minutes after the induction of LTP are shown on top. (B) LTP elicited in the presence of oligomerized Aβ1-42 (positive control). (C) LTP elicited in the presence of Aβ1-16. Scale bars represent 5 ms and 0.1 mV. (D) Comparison between LTP 60 minutes after the induction in control, in Aβ1-16 and in Aβ1-42.
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Figure 6: Aβ1-16 does not inhibit hippocampal long-term potentiation (LTP). (A) Control LTP elicited by three trains (20 impulses, 50 Hz) separated by 5 seconds. Data points are normalized field EPSP initial slope measurements ± standard errors of the mean. Average (n = 20) field EPSPs before and 60 minutes after the induction of LTP are shown on top. (B) LTP elicited in the presence of oligomerized Aβ1-42 (positive control). (C) LTP elicited in the presence of Aβ1-16. Scale bars represent 5 ms and 0.1 mV. (D) Comparison between LTP 60 minutes after the induction in control, in Aβ1-16 and in Aβ1-42.

Mentions: One of the hallmark synaptotoxic effects of Aβ1-42 is the inhibition of long-term potentiation (LTP) [25]. Results presented here, together with earlier data from our group [16], showing elevated CSF levels of Aβ1-16 in AD, prompted us to test whether the Aβ1-16 peptide per se inhibits LTP. To that end, we exposed acute rat hippocampal slices to Aβ1-16 and elicited LTP at the glutamatergic synapses in the CA1 region. Under our control conditions, a strong LTP-inducing protocol (three times 20 impulses at 50 Hz during blockade of GABAA receptors) resulted in LTP that amounted to 130 ± 7.3% (presynaptic volley = 97 ± 3.5%, n = 7) 60 minutes after the induction (Figure 6A, D). As a positive control, we exposed the slice to Aβ1-42 oligomers (prepared from 1 μM monomeric Aβ1-42, see Methods) for 30-60 minutes before the induction of LTP. Under these conditions the LTP was 103 ± 5.9% (presynaptic volley = 90.5 ± 1.6%, n = 6), which was significantly smaller than control (P = 0.017) (Figure 6B, D). To test whether Aβ1-16 affects the generation of LTP, we exposed the slice to Aβ1-16 (1 μg/L) for 60 minutes before the induction. The absolute endogenous concentration of Aβ1-16 in human CSF is 10-50 ng/L [15], but the synaptic concentration is not known. Therefore, to ascertain a not too low synaptic concentration of Aβ1-16, we used a concentration 20-100 times the absolute endogenous concentration of Aβ1-16 in human CSF. In the presence of Aβ1-16, LTP was 141 ± 3.6% (presynaptic volley = 100 ± 2.5%, n = 12) (Figure 6C, D), which is not significantly different from the control (P = 0.12). Hence, we conclude that Aβ1-16 does not inhibit LTP at hippocampal CA3-CA1 synapses.


Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.

Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H - Mol Neurodegener (2010)

Aβ1-16 does not inhibit hippocampal long-term potentiation (LTP). (A) Control LTP elicited by three trains (20 impulses, 50 Hz) separated by 5 seconds. Data points are normalized field EPSP initial slope measurements ± standard errors of the mean. Average (n = 20) field EPSPs before and 60 minutes after the induction of LTP are shown on top. (B) LTP elicited in the presence of oligomerized Aβ1-42 (positive control). (C) LTP elicited in the presence of Aβ1-16. Scale bars represent 5 ms and 0.1 mV. (D) Comparison between LTP 60 minutes after the induction in control, in Aβ1-16 and in Aβ1-42.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Aβ1-16 does not inhibit hippocampal long-term potentiation (LTP). (A) Control LTP elicited by three trains (20 impulses, 50 Hz) separated by 5 seconds. Data points are normalized field EPSP initial slope measurements ± standard errors of the mean. Average (n = 20) field EPSPs before and 60 minutes after the induction of LTP are shown on top. (B) LTP elicited in the presence of oligomerized Aβ1-42 (positive control). (C) LTP elicited in the presence of Aβ1-16. Scale bars represent 5 ms and 0.1 mV. (D) Comparison between LTP 60 minutes after the induction in control, in Aβ1-16 and in Aβ1-42.
Mentions: One of the hallmark synaptotoxic effects of Aβ1-42 is the inhibition of long-term potentiation (LTP) [25]. Results presented here, together with earlier data from our group [16], showing elevated CSF levels of Aβ1-16 in AD, prompted us to test whether the Aβ1-16 peptide per se inhibits LTP. To that end, we exposed acute rat hippocampal slices to Aβ1-16 and elicited LTP at the glutamatergic synapses in the CA1 region. Under our control conditions, a strong LTP-inducing protocol (three times 20 impulses at 50 Hz during blockade of GABAA receptors) resulted in LTP that amounted to 130 ± 7.3% (presynaptic volley = 97 ± 3.5%, n = 7) 60 minutes after the induction (Figure 6A, D). As a positive control, we exposed the slice to Aβ1-42 oligomers (prepared from 1 μM monomeric Aβ1-42, see Methods) for 30-60 minutes before the induction of LTP. Under these conditions the LTP was 103 ± 5.9% (presynaptic volley = 90.5 ± 1.6%, n = 6), which was significantly smaller than control (P = 0.017) (Figure 6B, D). To test whether Aβ1-16 affects the generation of LTP, we exposed the slice to Aβ1-16 (1 μg/L) for 60 minutes before the induction. The absolute endogenous concentration of Aβ1-16 in human CSF is 10-50 ng/L [15], but the synaptic concentration is not known. Therefore, to ascertain a not too low synaptic concentration of Aβ1-16, we used a concentration 20-100 times the absolute endogenous concentration of Aβ1-16 in human CSF. In the presence of Aβ1-16, LTP was 141 ± 3.6% (presynaptic volley = 100 ± 2.5%, n = 12) (Figure 6C, D), which is not significantly different from the control (P = 0.12). Hence, we conclude that Aβ1-16 does not inhibit LTP at hippocampal CA3-CA1 synapses.

Bottom Line: SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information.PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

ABSTRACT

Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups.

Results: We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.

Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

No MeSH data available.


Related in: MedlinePlus